Bevantolol ((±)-bevantolol; DL-bevantolol; NSC 132348; 1-[[2-(3,4-dimethoxyphenyl)ethyl]amino]-3-(3-methylphenoxy)-2-propanol; CAS #59170-23-9) is a vesicular monoamine transporter 2 (VMAT2) inhibitor. Bevantolol has shown promise in treating chronic hyperkinetic movement disorders, Tourette's syndrome, Parkinson's disease, Huntington's disease, Huntington's chorea, Sydenham's chorea, tardive dyskinesia/dystonia, Parkinson's disease levodopa-induced dyskinesia, levodopa-induced dyskinesia, ataxia, corticobasal degeneration, dyskinesias (paroxysmal), dystonia (general, segmental, focal) including blepharospasm, spasmodic torticollis (cervical dystonia), writer's cramp (limb dystonia), laryngeal dystonia (spasmodic dysphonia), and oromandibular dystonia, essential tremor, hereditary spastic paraplegia, multiple system atrophy (Shy Drager Syndrome), myoclonus, progressive supranuclear palsy, restless legs syndrome, Rett Syndrome, spasticity due to stroke, cerebral palsy, multiple sclerosis, spinal cord or brain injury, tics, Wilson's Disease, oppositional defiant disorder, Huntington's disease like diseases (HDL1, HDL2 and HDL3), benign hereditary chorea, neuroacanthocytosis, neurodegeneration with brain iron accumulation (NBIA), athetosis, Friedreich ataxia, spinocerebellar ataxia, multiple system atrophy, dentatorubral-pallidoluysian atrophy, ataxia with oculomotor apraxia (types 1 and 2), ataxia telangiectasia, focal dystonias, idiopathic dystonias such as Oppenheim dystonia and torticollis, dystonia-plus syndromes, secondary dystonias, Duchenne muscular dystrophy, and Down syndrome. WO 2014202646.
Bevantolol is also known as a beta-1 adrenoreceptor antagonist (Vaughan Williams, “Bevantolol: a beta-1 adrenoreceptor antagonist with unique additional actions”, J. Clin. Pharmacol. 1987, 27, 450-460) and calcium channel blocker (T. Omura, T. Kobayashi, K. Nishioka, N. Miyake, N. Akaike, “Ca(2+)-antagonistic action of bevantolol on hypothalamic neurons in vitro: its comparison with those of other beta-adrenoreceptor antagonists, a local anesthetic and a Ca(2+)-antagonist”, Brain Res. 1996, 706, 289-292). By virtue of these actions bevantolol is useful for the treatment of hypertension and angina pectoris. (W. H. Fishman, R. J. Goldberg, P. Benfield, “Bevantolol. A preliminary review of its pharmacodynamics and pharmacokinetic properties, and therapeutic efficacy in hypertension and angina pectoris”, Drugs, 1988, 35, 1-21; H. Kaplan, “Pharmacology of bevantolol hydrochloride”, Am. J. Cardiol. 1986, 58, E3-E7.) It is approved for example in the US, Great Britain, France and Japan for the treatment of hypertension and angina pectoris from coronary heart disease.

Bevantolol is subject to extensive CYP450-mediated oxidative metabolism, including hydroxylation of the methyl-bearing phenyl ring, hydroxylation of the aromatic methyl group, followed by further oxidation to the carboxylic acid, and oxidative demethylation of the methoxy groups. Kaplan et al., New Drugs Annual: Cardiovascular Drugs, 1985, Vol. 3. Latts, J. R., Clinical Pharmacokinetics and Metabolism of Bevantolol, Angiology—Journal of Vascular Diseases, March 1986, p. 221-225.
Deuterium Isotope Effect
In order to eliminate foreign substances such as therapeutic agents, the animal body expresses various enzymes, such as the cytochrome P450 enzymes (CYPs), esterases, proteases, reductases, dehydrogenases, and monoamine oxidases, to react with and convert these foreign substances to more polar intermediates or metabolites for renal excretion. Such metabolic reactions frequently involve the oxidation of a carbon-hydrogen (C—H) bond to either a carbon-oxygen (C—O) or a carbon-carbon (C—C) □-bond. The resultant metabolites may be stable or unstable under physiological conditions, and can have substantially different pharmacokinetic, pharmacodynamic, and acute and long-term toxicity profiles relative to the parent compounds. For most drugs, such oxidations are generally rapid and ultimately lead to administration of multiple or high daily doses.
The relationship between the activation energy and the rate of reaction may be quantified by the Arrhenius equation, k=Ae−Eact/RT. The Arrhenius equation states that, at a given temperature, the rate of a chemical reaction depends exponentially on the activation energy (Eact).
The transition state in a reaction is a short lived state along the reaction pathway during which the original bonds have stretched to their limit. By definition, the activation energy Eact for a reaction is the energy required to reach the transition state of that reaction. Once the transition state is reached, the molecules can either revert to the original reactants, or form new bonds giving rise to reaction products. A catalyst facilitates a reaction process by lowering the activation energy leading to a transition state. Enzymes are examples of biological catalysts.
Carbon-hydrogen bond strength is directly proportional to the absolute value of the ground-state vibrational energy of the bond. This vibrational energy depends on the mass of the atoms that form the bond, and increases as the mass of one or both of the atoms making the bond increases. Since deuterium (D) has twice the mass of protium (1H), a C-D bond is stronger than the corresponding C—1H bond. If a C—1H bond is broken during a rate-determining step in a chemical reaction (i.e. the step with the highest transition state energy), then substituting a deuterium for that protium will cause a decrease in the reaction rate. This phenomenon is known as the Deuterium Kinetic Isotope Effect (DKIE). The magnitude of the DKIE can be expressed as the ratio between the rates of a given reaction in which a C—1H bond is broken, and the same reaction where deuterium is substituted for protium. The DKIE can range from about 1 (no isotope effect) to very large numbers, such as 50 or more. Substitution of tritium for hydrogen results in yet a stronger bond than deuterium and gives numerically larger isotope effects.
Deuterium (2H or D) is a stable and non-radioactive isotope of hydrogen which has approximately twice the mass of protium (1H), the most common isotope of hydrogen. Deuterium oxide (D2O or “heavy water”) looks and tastes like H2O, but has different physical properties.
When pure D2O is given to rodents, it is readily absorbed. The quantity of deuterium required to induce toxicity is extremely high. When about 0-15% of the body water has been replaced by D2O, animals are healthy but are unable to gain weight as fast as the control (untreated) group. When about 15-20% of the body water has been replaced with D2O, the animals become excitable. When about 20-25% of the body water has been replaced with D2O, the animals become so excitable that they go into frequent convulsions when stimulated. Skin lesions, ulcers on the paws and muzzles, and necrosis of the tails appear. The animals also become very aggressive. When about 30% of the body water has been replaced with D2O, the animals refuse to eat and become comatose. Their body weight drops sharply and their metabolic rates drop far below normal, with death occurring at about 30 to about 35% replacement with D2O. The effects are reversible unless more than thirty percent of the previous body weight has been lost due to D2O. Studies have also shown that the use of D2O can delay the growth of cancer cells and enhance the cytotoxicity of certain antineoplastic agents.
Deuteration of pharmaceuticals to improve pharmacokinetics (PK), pharmacodynamics (PD), and toxicity profiles has been demonstrated previously with some classes of drugs. For example, the DKIE was used to decrease the hepatotoxicity of halothane, presumably by limiting the production of reactive species such as trifluoroacetyl chloride. However, this method may not be applicable to all drug classes. For example, deuterium incorporation can lead to metabolic switching. Metabolic switching occurs when xenogens, sequestered by Phase I enzymes, bind transiently and re-bind in a variety of conformations prior to the chemical reaction (e.g., oxidation). Metabolic switching is enabled by the relatively vast size of binding pockets in many Phase I enzymes and the promiscuous nature of many metabolic reactions. Metabolic switching can lead to different proportions of known metabolites as well as altogether new metabolites. This new metabolic profile may impart more or less toxicity. Such pitfalls are non-obvious and are not predictable a priori for any drug class.
Bevantolol is a vesicular monoamine transporter 2 (VMAT2) inhibitor. The carbon-hydrogen bonds of bevantolol contain a naturally occurring distribution of hydrogen isotopes, namely 1H or protium (about 99.9844%), 2H or deuterium (about 0.0156%), and 3H or tritium (in the range between about 0.5 and 67 tritium atoms per 1018 protium atoms). Increased levels of deuterium incorporation may produce a detectable Deuterium Kinetic Isotope Effect (DKIE) that could affect the pharmacokinetic, pharmacologic and/or toxicologic profiles of such bevantolol in comparison with the compound having naturally occurring levels of deuterium.
Based on discoveries made in our laboratory, as well as considering the literature, bevantolol is likely metabolized in humans at the aromatic methyl and methoxy groups, the methyl-bearing phenyl ring, the benzylic methylene group, the N-methylene groups, the O-methylene group, and the O-methine group. The current approach has the potential to prevent metabolism at these sites. Other sites on the molecule may also undergo transformations leading to metabolites with as-yet-unknown pharmacology/toxicology. Limiting the production of these metabolites has the potential to decrease the danger of the administration of such drugs and may even allow increased dosage and/or increased efficacy. All of these transformations can occur through polymorphically-expressed enzymes, exacerbating interpatient variability. Further, some disorders are best treated when the subject is medicated around the clock or for an extended period of time. For all of the foregoing reasons, a medicine with a longer half-life may result in greater efficacy and cost savings. Various deuteration patterns can be used to (a) reduce or eliminate unwanted metabolites, (b) increase the half-life of the parent drug, (c) decrease the number of doses needed to achieve a desired effect, (d) decrease the amount of a dose needed to achieve a desired effect, (e) increase the formation of active metabolites, if any are formed, (f) decrease the production of deleterious metabolites in specific tissues, and/or (g) create a more effective drug and/or a safer drug for polypharmacy, whether the polypharmacy be intentional or not. The deuteration approach has the strong potential to slow the metabolism of bevantolol and attenuate interpatient variability.
Novel compounds and pharmaceutical compositions, certain of which have been found to block calcium channel or beta adrenoreceptor activity, and/or to inhibit VMAT2 have been discovered, together with methods of synthesizing and using the compounds, including methods for the treatment of disorders in a patient by administering the compounds.